Efficacy of Nonpharmacological Interventions in Cognitive Impairment: Systematic Review And Network Meta-Analysis.

INTRODUCTION: There is currently no known cure for cognitive impairment, which highlights the need to explore other ways of managing this condition. This topic has recently become an area of active research. However, the availability of nonpharmacological options poses a challenge when trying to determine the best treatment for improving cognitive function. METHODS: We conducted a systematic review and a Bayesian network meta-analysis to compare the effects of nonpharmacological interventions on global cognition in patients with mild cognitive impairment and dementia. The nonpharmacological interventions were classified as aerobic exercise, strength exercise, multicomponent physical exercise, other physical exercises, tai chi, mind-body exercises, traditional cognitive rehabilitation, computer-based cognitive rehabilitation, occupational therapy, music therapy, physical-cognitive rehabilitation, and reminiscence therapy. RESULTS: Physical-cognitive rehabilitation emerged as the most effective nonpharmacological intervention for enhancing global cognition in patients with unspecified cognitive impairment and dementia, whereas occupational therapy focused on dual-task interventions was found to be the most effective nonpharmacological intervention for mild cognitive impairment. CONCLUSION: These results underscore the importance of adopting a dual approach to managing cognitive impairment, integrating both cognitive and physical rehabilitation within the same intervention.

Evaluation of concordance of new QuantiFERON-TB Gold Plus platforms for Mycobacterium tuberculosis infection diagnosis in a prospective cohort of household contacts.

Interferon-gamma (IFN-γ) release assays play a pivotal role in tuberculosis infection (TBI) diagnosis, with QuantiFERON-TB Gold Plus-an enzyme-linked immunosorbent assay (ELISA)-among the most widely utilized. Newer QuantiFERON-TB platforms with shorter turnaround times were recently released. We aimed to evaluate these platforms' agreement in the diagnosis of TBI. Blood samples from a prospective cohort of tuberculosis household contacts were collected at baseline and after 12 weeks of follow-up, and tested with LIAISON, an automated chemiluminescence immunoassay (CLIA) system, QIAreach, a lateral flow (QFT-LF) semi-automated immunoassay, and the ELISA QuantiFERON-TB Gold Plus platform. Test concordances were analyzed. ELISA vs CLIA overall agreement was 83.3% for all tested samples (120/144) [Cohen's kappa coefficient (κ): 0.66 (95% CI: 0.54-0.77)]. Samples positive with CLIA provided consistently higher IFN-γ levels than with ELISA (P < 0.001). Twenty-four (16.7%) discordant pairs were obtained, all CLIA-positive/ELISA-negative: 15 (62.5%) had CLIA IFN-γ levels within borderline values (0.35-0.99 IU/mL) and 9 (37.5%) >0.99 IU/mL. QFT-LF showed only 76.4% (68/89) overall agreement with ELISA [κ: 0.53 (95% CI: 0.37-0.68)] with 21 (23.6%) discordant results obtained, all QFT-LF-positive/ELISA-negative. Overall concordance between ELISA and CLIA platforms was substantial, and only moderate between ELISA and QFT-LF. The CLIA platform yielded higher IFN-γ levels than ELISA, leading to an almost 17% higher positivity rate. The techniques do not seem interchangeable, and validation against other gold standards, such as microbiologically-confirmed tuberculosis disease, is required to determine whether these cases represent true new infections or whether CLIA necessitates a higher cutoff. IMPORTANCE: Tuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis that affects over 10 million people annually, with over 2 billion people carrying an asymptomatic tuberculosis infection (TBI) worldwide. Currently, TBI diagnosis includes tuberculin skin test and the blood-based interferon-gamma (IFN-γ) release assays, with Qiagen QuantiFERON-TB Gold Plus (QFT) being among those most widely utilized. We evaluated Qiagen's newer QFT platforms commercially available in a prospective cohort of tuberculosis contacts. A substantial agreement was obtained between the current QFT-enzyme-linked immunosorbent assay (ELISA) and the new QFT-chemiluminescence immunoassay (CLIA) platform, although QFT-CLIA provided higher concentrations of IFN-γ, leading to a 16.6% higher positivity rate. We highlight that both platforms may not be directly interchangeable and that further validation is required.

[Improving the nutritional care of oncology patients - Validation of a multidisciplinary protocol in the Spanish clinical setting]. / Mejorando la atención nutricional del paciente oncológico: validación de un protocolo multidisciplinar en el entorno clínico español.

INTRODUCTION: malnutrition is a very frequent problem in oncology patients and can have serious repercussions. Adequate nutritional management is cost-effective in terms of health and survival in this population, but it requires multidisciplinary coordination, specific training, and continuous follow-up. OBJECTIVE: to validate the applicability and efficacy of a multidisciplinary nutritional support protocol in oncology patients. METHODS: a multidisciplinary nutritional protocol was developed for oncology patients, with guidelines for screening and assessment of malnutrition, treatment, re-evaluation, and management of side effects, as well as guidance on supplementation and eating patterns. The protocol would be implemented in various clinical centers, collecting data through a structured questionnaire, registering variables before and after implementation. RESULTS: the protocol and its impact were implemented and evaluated in 39 centers. An improvement in nutritional care was observed, evidenced by an earlier initiation of nutritional assessment and an increase in the number of patients receiving adequate care following the protocol implementation. Problems related to inadequate malnutrition coding in the centers, limited resources, and the need for greater interdepartmental collaboration were identified. CONCLUSIONS: the conduct of this study provides insights into how the implementation of a multidisciplinary nutritional support protocol can improve the nutritional care received by patients and informs about the main obstacles to adequate implementation.

Academic accountability to local communities and society through Programme Science: a case study from the HPV self-sampling programme HOPE in Peru.

INTRODUCTION: Health challenges in the 21st century underscore the need for adaptable and innovative approaches in public health. Academic institutions can and should contribute much more effectively to generate and translate scientific knowledge that will result in better programmes to improve societal health. Academic accountability to local communities and society requires universities to actively engage with local communities, understanding the context, their needs, and leveraging their knowledge and local experience. The Programme Science initiative provides a framework to optimize the scale, quality and impact of public health programmes, by integrating diverse approaches during the iterative cycle of research and practice within the strategic planning, programme implementation and programme management and evaluation. We illustrate how the Programme Science framework could be a useful tool for academic institutions to accomplish accountability to local communities and society through the experience of Project HOPE in Peru. DISCUSSION: Project HOPE applied the Programme Science framework to introduce HPV self-sampling into a women's health programme in Peru. Collaboration with local authorities and community members was pivotal in all phases of the project, ensuring interventions aligned with community needs and addressing social determinants of health. The HOPE Ladies-community women trained and empowered to promote and provide the HPV kits-crafted the messages used through the study and developed strategies to reach individuals and provided support to women's journey through health centres. By engaging communities in co-creating knowledge and addressing health inequities, academic institutions can generate contextually relevant and socially just scientific knowledge. The active participation of community women in Project HOPE was instrumental in improving service utilization and addressing barriers to self-sampling. CONCLUSIONS: The Programme Science approach offers a pathway for academic institutions to enhance their accountability to communities and society at large. By embedding researchers within public health programmes and prioritizing community engagement, academic institutions can ensure that research findings directly inform policy improvements and programmatic decisions. However, achieving this requires a realignment of research agendas and recognition of the value of community engagement. Establishing Programme Science networks involving academia, government and funding entities can further reinforce academic accountability and enhance the impact of public health programmes.

Silver-enriched microdomain patterns as advanced bactericidal coatings for polymer-based medical devices.

Today, it would be difficult for us to live a full life without polymers, especially in medicine, where its applicability is constantly expanding, giving satisfactory results without any harm effects on health. This study focused on the formation of hexagonal domains doped with AgNPs using a KrF excimer laser (λ=248 nm) on the polyetheretherketone (PEEK) surface that acts as an unfailing source of the antibacterial agent - silver. The hexagonal structure was formed with a grid placed in front of the incident laser beam. Surfaces with immobilized silver nanoparticles (AgNPs) were observed by AFM and SEM. Changes in surface chemistry were studied by XPS. To determine the concentration of released Ag+ ions, ICP-MS analysis was used. The antibacterial tests proved the antibacterial efficacy of Ag-doped PEEK composites against Escherichia coli and Staphylococcus aureus as the most common pathogens. Because AgNPs are also known for their strong toxicity, we also included cytotoxicity tests in this study. The findings presented here contribute to the advancement of materials design in the biomedical field, offering a novel starting point for combating bacterial infections through the innovative integration of AgNPs into inert synthetic polymers.

Selective Synthesis of Boron-Functionalized Indenes and Benzofulvenes by BCl3-Promoted Cyclizations of ortho-Alkynylstyrenes.

A selective, metal-free synthesis of boron-functionalized indenes and benzofulvenes via BCl3-mediated cyclization of o-alkynylstyrenes is described. The method allows precise control over product formation by adjusting reaction conditions. These borylated products were utilized in diverse C-B bond derivatizations and in the total synthesis of Sulindac, a nonsteroidal anti-inflammatory drug, demonstrating the versatility and practicality of the developed methodology for synthetic applications.

Exosomes Exposed: Overview Systematic Review on Evidence Versus Expectation in Aesthetic and Regenerative Medicine.

INTRODUCTION: Exosomes, diminutive extracellular vesicles, are integral to intercellular communication, harbouring potential for applications in regenerative medicine and aesthetic interventions. The field, however, grapples with the complexities of harmonising exosome characterisation protocols and safeguarding therapeutic integrity. METHODOLOGY: In this scholarly overview, systematic adherence to the Cochrane Collaboration and Preferred Reporting Items for Overviews of Reviews guidelines was observed, scrutinising the congruence of exosome-related therapies with the Minimal Information for Studies of Extracellular Vesicles standards delineated by the International Society for Extracellular Vesicles, alongside criteria set forth by the International Society for Cell Therapy and the International Society for Stem Cell Research. A meticulous search strategy spanning databases such as PubMed, Scopus, Web of Science, EMBASE, and Cochrane database was employed to encapsulate studies pertinent to the isolation, characterisation, and functional assessment of exosomes. RESULTS: The initial search yielded 225 articles, of which 17 systematic reviews were selected based on predefined criteria, encompassing 556 primary studies. Notwithstanding the acknowledged therapeutic promise of exosome modalities, the synthesis illuminated a prevalent deficiency in adherence to established reporting and experimental benchmarks, notably in exosome source characterisation and bioactive constituent delineation. A critical appraisal employing the AMSTAR-2 tool underscored a pervasive shortfall in methodological rigour. CONCLUSION: This review accentuates the imperative for stringent methodological standardisation within exosome research to fortify the validity and reproducibility of empirical findings. Amidst the burgeoning therapeutic optimism, the discipline must rectify methodological disparities and comply with regulatory mandates, ensuring the ethically sound and scientifically robust advancement of exosome-based therapeutic modalities. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article.  For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Generational Exploration on Aesthetic Medicine Products: Influence of Social Media, Reviews, and Brand Identity-GEMS Bond Survey.

INTRODUCTION: The study investigates the impact of social media reviews and brand identity on consumer preferences in the non-surgical aesthetics products across different generations. It highlights the evolving landscape of aesthetic medicine and surgery, driven by technological advancements and a cultural shift towards individual well-being. The research aims to explore the interplay between generational preferences, the influence of social media, and the role of brand identity in shaping consumer decisions. METHODS: A cross-sectional study design was employed, with a sample size of > 5000 participants stratified across various generational cohorts. The study utilized an online questionnaire to capture both quantitative and qualitative insights into consumer behaviour, with statistical analysis performed to identify patterns and relationships. RESULTS: Analysis of 5850 responses revealed distinct generational preferences and behaviours. Social media engagement varied significantly across generations, with younger cohorts placing a higher emphasis on online reviews. The study also found that brand identity's influence is diminishing in decision-making processes, with consumers increasingly relying on peer reviews and social media content. CONCLUSION: The findings highlight a pivotal shift in the non-surgical aesthetics consumer market, emphasizing the growing importance of social media and peer reviews over traditional brand identities. Importantly, the study underscores the critical need for integrating patient safety and evidence-based practice within marketing strategies. As consumer preferences evolve towards valuing transparency and authenticity, non-surgical aesthetics providers must prioritize these elements, ensuring that their services are not only appealing but also grounded in safety and scientific validity. LEVEL OF EVIDENCE IV: "This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ."

Cattel and Blumgart Anastomosis: Comparison of Pancreatojejunostomy Techniques in Patients with Pancreatic Cancer.

BACKROUND: Pancreaticojejunal anastomosis has a high risk of pancreatic leakage, which several surgical techniques have been described. Our main objective is to determine what is the association of postoperative pancreatic leakage in patients undergoing pancreaticoduodenectomy according to the pancreaticojejunal anastomosis technique used (Cattel vs Blumgart)? MATERIAL AND METHODS: Historical cohort, all cancer patients undergoing pancreaticoduodenectomy were included. From April 2020 to May 2021, Cattel technique was used; from June 2021 to June 2022, Blumgart technique was used. All procedures were performed by a single board-certified surgical oncologist at Oncology Hospital. RESULTS: 24 patients (11 men and 13 women). The first 9 procedures were performed with the Cattel technique, starting from procedure 10, the Blumgart technique was used. No differences were observed regarding the consistency of the pancreas (p=0.28) or the size of the duct (p=0.51) between the two groups. Pancreatic leakage was observed in 100% with the Cattel technique and in 6.7% with the Blumgart technique (p= 0.0001). An amylase value was observed in the left drainage at 6 days > 200 U/L with the Cattel technique and < 200 U/L with Blumgart (p=0.0001). Intraoperative bleeding (Cattel 1200 ml vs. Blumgart 400 ml, p= 0.03) and 90-day mortality (Cattel 33.3% vs. Blumgart 0%, Log-Rank: 0.022) also showed a difference in favor of Blumgart technique. Blumgart technique is a protective factor for the presence of pancreatic leakage (RR 0.06, 95% CI 0.01-0.44, p=0.0001). DISCUSSION: A lower risk of pancreatic leakage was found using the Blumgart technique, compared to the Cattel technique.

Correction: University engagement of dental students related to educational environment: A transnational study.

[This corrects the article DOI: 10.1371/journal.pone.0259524.].

Conventional and microfluidic methods: Design and optimization of lipid-polymeric hybrid nanoparticles for gene therapy.

Gene therapy holds significant promise as a therapeutic approach for addressing a diverse range of diseases through the suppression of overexpressed proteins and the restoration of impaired cell functions. Developing a nanocarrier that can efficiently load and release genetic material into cells remains a challenge. The primary goal of this study is to develop formulations aimed to enhance the therapeutic potential of GapmeRs through technological approaches. To this end, lipid-polymeric hybrid nanoparticles (LPHNPs) with PLGA, DC-cholesterol, and DOPE-mPEG2000 were produced by conventional single-step nanoprecipitation (SSN) and microfluidic (MF) methods. The optimized nanoparticles by SSN have a size of 149.9 ± 18.07 nm, a polydispersity index (PdI) of 0.23 ± 0.02, and a zeta potential of (ZP) of 29.34 ± 2.44 mV, while by MF the size was 179.8 ± 6.3, a PdI of 0.24 ± 0.01, and a ZP of 32.25 ± 1.36 mV. Furthermore, LPHNPs prepared with GapmeR-protamine by both methods exhibit a high encapsulation efficiency of approximately 90%. The encapsulated GapmeR is completely released in 24 h. The LPHNP suspensions are stable for up to 6 h in 10% FBS at pH 5.4 and 7.4. By contrast, LPHNPs remain stable in suspension in 4.5% albumin at pH 7.4 for 24 h. Additionally, LPHNPs were successfully freeze-dried using trehalose in the range of 2.5-5% as cryoprotectant The LPHNPs produced by MF and SSN increase, 6 and 12 fold respectively, GapmeR cell uptake, and both of them reduce by 60-70% expression of Tob1 in 48 h.Our study demonstrates the efficacy of the developed LPHNPs as carriers for oligonucleotide delivery, offering valuable insights for their scale up production from a conventional bulk methodology to a high-throughput microfluidic technology.

Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa.

Introduction: Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant Pseudomonas aeruginosa, particularly those that are carbapenem resistant. CZA resistance in P. aeruginosa producing PER, a class A extended-spectrum ß-lactamase, has been well documented in vitro. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing P. aeruginosa clinical isolates that were ceftazidime and/or carbapenem non-susceptible. Methods: Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while bla PER gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of bla PER-3 gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. Results: Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried bla PER. One isolate carried bla PER but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their bla PER-3 gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum ß-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of bla PER-3 gene restored susceptibility to CZA, ceftolozane/tazobactam and other ß-lactamsin the in vitro evolved isolate. Discussion: PER-3-producing ST309 P. aeruginosa is a successful multidrug-resistant clone with blaPER-3 gene implicated in resistance to CZA and other ß-lactams.

miRNome profiling of extracellular vesicles in severe COVID-19 patients and identification of predictors of mortality.

BACKGROUND: Extracellular vesicles (EVs), containing microRNAs (miRNAs) and other molecules, play a central role in intercellular communication, especially in viral infections caused by SARS-CoV-2. This study explores the miRNA profiles in plasma-derived EVs from severe COVID-19 patients referred to controls, identifying potential mortality miRNA predictors. METHODS: A prospective study was carried out, including 36 severe COVID-19 patients and 33 non-COVID-19 controls. EVs-derived miRNAs were sequenced, and bioinformatics and differential expression analysis between groups were performed. The plasma miRNA profile of an additional cohort of severe COVID-19 patients (n=32) and non-COVID-19 controls (n=12) was used to compare with our data. Survival analysis was used to identify potential mortality predictors among the SDE miRNAs in EVs. RESULTS: Severe COVID-19 patients showed 50 significantly differentially expressed (SDE) miRNAs in plasma-derived EVs. These miRNAs were associated with pathways related to inflammation and cell adhesion. Fifteen of these plasma-derived EVs miRNAs were also SDE in the plasma of severe patients vs controls. Two miRNAs, hsa-miR-1469 and hsa-miR-6124, were identified as strong mortality predictors with an área under the ROC Curve (AUC) of 0.938. CONCLUSION: : This research provides insights into the role of miRNAs found within EVs in severe COVID-19 and their potential as clinical biomarkers for mortality.

Global Water Challenges in Sub-Saharan Africa and how to strengthen science-policy dialogues on transboundary governance and cooperation.

The United Nations Water Conference 2023 highlighted the need for concrete actions to boost integrated water resources management for achieving the Sustainable Development Goals and called for strategies to enhance cooperation among stakeholders. Technical cooperation between countries and institutions in transboundary systems, e.g., on environmental data collection, is an effective way to promote international diplomacy and prevent disputes between riparian states. Still, establishing collaborations to inform bilateral dialogues on the identification of environmental challenges, their causes, and development priorities may be a difficult task in itself. This is particularly true in the African context because of limited resources and lack of data. In this paper, we analyse the case of nine transboundary river basins in Sub-Saharan Africa to identify which water-management challenges are perceived as most important by the different riparian countries from a policy and scientific perspective. Our insights are based on the most up-to-date scientific papers, open access reports and technical literature, river basin authority's strategy papers, projects' summary reports, and national policy documents. We also complement these sources with the pieces of information we gained through collaborations with regional and local experts, and management bodies (such as river basin authorities). We highlight the current water-related conflicts and the gap between the priorities identified by the scientific community and different riparian countries on how to tackle hydro-climatic change and improve food and energy security, human and environmental health. Based on our experience, we discuss some keys to building trust among stakeholders, strengthening cooperation, and identifying shared water-governance measures in transboundary river basins. They are: (i) connect science and policy to provide sound knowledge for the right questions, (ii) value local knowledge and exploit the complementarity of different perspectives, (iii) consider multiple spatial scales and multi-level stakeholders to leave no one behind, (iv) promote a culture which values trade-offs and handles complexity, and (v) co-create data and knowledge to facilitate stakeholder dialogue from problem definition to intervention identification.

LINC00662 Promotes Aggressive Traits by Modulating OCT4 Expression through miR-335-5p in Gallbladder Cancer Cells.

Long non-coding RNAs (lncRNAs) are nucleotide sequences that participate in different biological processes and are associated with different pathologies, including cancer. Long intergenic non-protein-coding RNA 662 (LINC00662) has been reported to be involved in different cancers, including colorectal, prostate, and breast cancer. However, its role in gallbladder cancer has not yet been described. In this article, we hypothesize that LINC00662 has an important role in the acquisition of aggressiveness traits such as a stem-like phenotype, invasion, and chemoresistance in gallbladder cancer. Here, we show that LINC00662 is associated with larger tumor size and lymph node metastasis in patients with gallbladder cancer. Furthermore, we show that the overexpression of LINC00662 promotes an increase in CD133+/CD44+ cell populations and the expression of stemness-associated genes. LINC00662 promotes greater invasive capacity and the expression of genes associated with epithelial-mesenchymal transition. In addition, the expression of LINC00662 promotes resistance to cisplatin and 5-fluorouracil, associated with increased expression of chemoresistance-related ATP-binding cassette (ABC) transporters in gallbladder cancer (GBC) cell lines. Finally, we show that the mechanism by which LINC00662 exerts its function is through a decrease in microRNA 335-5p (miR-335-5p) and an increase in octamer-binding transcription factor 4 (OCT4) in GBC cells. Thus, our data allow us to propose LINC00662 as a biomarker of poor prognosis and a potential therapeutic target for patients with GBC.

A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.

The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

Population assessment of health system performance in 16 countries.

Objective: To demonstrate how the new internationally comparable instrument, the People's Voice Survey, can be used to contribute the perspective of the population in assessing health system performance in countries of all levels of income. Methods: We surveyed representative samples of populations in 16 low-, middle- and high-income countries on health-care utilization, experience and confidence during 2022-2023. We summarized and visualized data corresponding to the key domains of the World Health Organization universal health coverage framework for health system performance assessment. We examined correlation with per capita health spending by calculating Pearson coefficients, and within-country income-based inequities using the slope index of inequality. Findings: In the domain of care effectiveness, we found major gaps in health screenings and endorsement of public primary care. Only one in three respondents reported very good user experience during health visits, with lower proportions in low-income countries. Access to health care was rated highest of all domains; however, only half of the populations felt secure that they could access and afford high-quality care if they became ill. Populations rated the quality of private health systems higher than that of public health systems in most countries. Only half of respondents felt involved in decision-making (less in high-income countries). Within countries, we found statistically significant pro-rich inequalities across many indicators. Conclusion: Populations can provide vital information about the real-world function of health systems, complementing other system performance metrics. Population-wide surveys such as the People's Voice Survey should become part of regular health system performance assessments.

The Alk receptor tyrosine kinase regulates Sparkly, a novel activity regulating neuropeptide precursor in the Drosophila central nervous system.

Numerous roles for the Alk receptor tyrosine kinase have been described in Drosophila, including functions in the central nervous system (CNS), however the molecular details are poorly understood. To gain mechanistic insight, we employed Targeted DamID (TaDa) transcriptional profiling to identify targets of Alk signaling in the larval CNS. TaDa was employed in larval CNS tissues, while genetically manipulating Alk signaling output. The resulting TaDa data were analyzed together with larval CNS scRNA-seq datasets performed under similar conditions, identifying a role for Alk in the transcriptional regulation of neuroendocrine gene expression. Further integration with bulk and scRNA-seq datasets from larval brains in which Alk signaling was manipulated identified a previously uncharacterized Drosophila neuropeptide precursor encoded by CG4577 as an Alk signaling transcriptional target. CG4577, which we named Sparkly (Spar), is expressed in a subset of Alk-positive neuroendocrine cells in the developing larval CNS, including circadian clock neurons. In agreement with our TaDa analysis, overexpression of the Drosophila Alk ligand Jeb resulted in increased levels of Spar protein in the larval CNS. We show that Spar protein is expressed in circadian (clock) neurons, and flies lacking Spar exhibit defects in sleep and circadian activity control. In summary, we report a novel activity regulating neuropeptide precursor gene that is regulated by Alk signaling in the Drosophila CNS.